2, 3, 17-trihydroxyestra-1, 3, 5 (10)-triene ethers and esters



l i r i branched-chain isomers thereof. 7 I p v alkan'oyl comprises the radicals exemplified'by formyl, 'acetyl, propionyl, butyryl, valeryl, caproyl, enan'thyl, caprylyl, and the branched-chainisomers thereof.

2,3,iv-rRniYnRoxvasruA-nasdoyrninivn ETHERS AND ESTERS Willard M. Hoehn, wilifietterln, assignor to G. n. Searle & C o., Chicago, 111., a corporation of Delaware wherein'R is selected from the group consisting of lower alkyl and benzylr'adicals, R is selected. from the group consistingof lbwer'alkyl and lower alkanoylradicals, and R is alower alkanoyl radical. 'The'radicals which arefrepresented by lower alkyl are, for example, methyl, ethyl, propyl, butyl, amyl, hexyl, heptyl, pctyl, and the The term lower 1 Suitable starting materials for the preparation' 'of the compounds of this invention are the lower .alkyland benzyl ethers of 2eacetyl-3-hydroxy-l7p-(lower,alkanoyloxy)estra-l,3,5(10)-trienes. ethers is described in US. Patent 2,846,453.

The 2-acetoxy-17,B(lower' alkanoyloxy)-3-(1ower al koxy) estra-1,3,5 (10)-trienes of this invention can be manufactured by treating the aforementioned 2-acetyl- 17p-(lower alkanoyloxy)-3-(lower (10)-trienes in benzenewith perbenzoic acid. As a specific example, ,17fl-acetoxy-2-acetyl-3-meth0xyestra-1,3,5 (10)-triene is treated with perbenzoic acid in benzene to yield 2, 17/3-diacetoxy-3-methoxyestra- 1,3,5 10 -triene.

The 2-acetoxy-3-benzyloxy-17fl-(lower alkanoyloxy)estra-1,3,5( 10) trieines of the present; invention can be prepared by"reacting the aforementioned 2-acetyl- 3.-ben zyloxy-l7plower alkanoyloxy) estra-1,3,5 (,1 trienes with 2-acetyl-3 -benzyloxyestra-1 ,3 1 0 )"-triene is reacted with a benzene solutionof perhe'nzoic acid to afford 3-benzyl oxy-2,17 3-diacetoxyestra-1,3 ,5( 10) -triene.

The 3-benzyloxy-2-(lower alkoxy) compounds of 'this invention can be prepared from the aforementioned 2- -acetoxy-B-benzyloxy-17,8-(lower alkanoyloxy)estra-l,3,5

alkoxy)estra-1,3,5

Unitad 5W5 .P tflfqi s I 2,945,868 Patented uly .19,

Treatment of thelatter compound in pyridine with acetic anhydride results in, l7B-acetoxy-3-benzyloxy-2-methoxyestra-l,3,5(10)-'triene.. j I

By a process similar to that described supra, the 2,3- dialkoxy-17 3-(lower alkanoyloxy) estra l ,3 ,5 10) -tn'enes of this invention can be prepared. In this case,,the 2- acetoxy-l'lfl-j lower alkanoy loxy) -3-(lower alkoxy) estra- 1,3,5 (10) triene's of this invention are treated with a ,di-

(lower alkyl) sulfate and sodium hydroxide to afford the corresponding '2,3 dialkoxyestra-1,3 ,5 l0 triene-l7p-ols.

, The latter compounds are treated with pyridine and an estra-l,3,5(l0)-triene ethers and esters. The compounds of this invention are represented by'the structural formula The preparation of these ample, 2,17B-diacetoxy3-methoxyestra l,3,5(10) triene is reacted with sodium hydroxide and dimethyl s'ulfate,'re-

sulting in 2,3-dimethoxyestra-1,3,5(10)-trien-17B ol. The

latter substance is treated in pyridine with aceticlanhydride to :yield l7 8-acetoxy-2,3-dimethoxyestra-1,3,5( 10)'- triene. t Y

. The compounds of this invention are useful as a result of their valuable pharmacological properties. They exhibit selective anti-cortisone activity for upon administrationiwith cortisone they inhibit its ability to promote a Coxsackie virus infection. I

The invention will appear more-fully from the examples which follow. These examples are set forth by way of illustration only and it will be, understood that the inven- .tion is not to be construed as limitedin spirit or in scope by the details contained therein asmanyrnodificationsin materials and methods will be apparent in this disclosure to thoseiskilledin the art, In these examples temperat ures,are given in-degrees centigrade C. Quantities of materials are expressedin parts by weightunless otherwise noted. v

j EXAMPLE *1,

2-'acetyl3-'butoxy-1 7fi-valeryl0xyestra-1,3,5 (1 0) -tri'ene A solution of 5 parts of 17;?3-acetoxy-2-acetyl-3 hydroxy- -estra-'l,3 ,5(l0) trien e in 300part's' of methanol is mixed with 200 parts of 20% aqueous sodium" hydroxide and 2.50 'parts ofdibutylfsulfatei The resultant mixture is stirred'at room temperature for eight hours,"m'ade alkaline withdilutesodium hydroxide solution, and extracted with ether. The etherlayer is washed with water, dried over anhydrous; sodium sulfate, and evaporated to dryness in vacuo.- The-residue is c'rystallizedfrom an ether-hexane so7lution to afford 2-acetyl-3-butoxyestra-'l,3,5(10)-trien- 1fl-o1.

A mixture of l part of 2-ac'etyl-3-butoxyesn'a-1,3,5 (10)-trien-17fl-0Lh50 partsof pyridine and 75 parts of valeric anhydride is heated on a steam bath for 16 hours. The reaction mixture is poured into 250 parts of water, then theiesultan't mixture extracted" with ether. .The ether solution is'washed successively with-water, dilute aqueous sodium hydroxide, and dilute hydrochloric acid; dried over anhydrousasodium i-sulfate and evaporated to dryness i n vacuo. Re crystallization of the residue from afford 3-benzyloxy 2-methoxyestra-1,3,5(10)-trien-17fl-ol. i

an "etliler-hexane"solution yields" -2 -acetyl-3 -butoxy-l 713- valeryloxyestra-1,3,5(l0) triene, which exhibits maxima in the ultra-violet at 258 and 3l7 millirnicrpns with extinctionfcoeflicients of S'ZOQand 360.0,. respectively. j'Its infra-red spectrum possesses maxima at 5.;'Z8-,'-6.02, 6.70,

8.00, 8.3 7, 9.7mm 11,95 microns; "EXAMPLEzffif cessively with 2% aqueous Sodium hydroxide and water, dried over anhydrous sodium sulfate, and evaporated'to dryness in vacuo. The gummy residue is dissolved in a benzene-Skellysolve A mixture and the solution passed through a silica gel chromatographic column. Elutio'n of the column with a 2% ethyl acetate in benzene solution,yields the .crudeproduct. Recrystallization of the crude material from an etherrpetroleum ether solution affords 2, 17p1diacetoxy-3-methoxyestra-1,3,5 (10)-triene, M.P.'131-132.'5.

By substituting 2-acety1-3 butoxy-l7fi-valeryloxyestra- 1,3,'5(1'0)-triene andproceeding according to the herein described process, 2-acetoxy-3-butoxy-17p valeryloxy- .estra-.1,3,5(-10)-.triene isv obtained. r t

- EXAMPLE '3' 3 -benzy Icky-2,1 7I3-diacetoxyestrd-1 ,3,5(] -triene .iTo anice-cold solution'of 5 parts of l7 8-acetoxy-2-acevtyl ii-benzyloxyestra-1,3,5(10)-triene in.=90 parts of hen- 'z ene:is .added asolution'of 3.26 parts of perbenzoic acid in'llOparts ofibenzene. The resultant solutiouis allowed to stand at room temperature for three days, then treated with200 parts of 5% aqueous sodium hydroxide and 140 parts of ether. The mixture-is shaken in a separatory funnel, the organic layer separated and 'washed successively with 5% aqueous sodium hydroxide and water. The ether solution is dried over anhydrous'sodiurn'sulfate, then concentrated to dryness under reduced pressure. The crystalline residue is recrystallized first from aqueous methanol, then from methanol to afford -3-benzyloxy-Z,17p-diacet0xyestra-l,3,5(10) triene, MP. 146- 148; [a] =+32.5 (1% in-chloroform);

By substituting-2-acetyl-3-benzyloxy-l7fl-butyroxyestra- 1,3,5 10)-triene and proceedingaccording'to the herein described process, 2-acetoxy-3-benzy1oxy-17B-butyroxy- To a solution of 7 parts of 3-benzyloxy-2,17;3-diacet oxyestra-1,3,5(10)-triene in 400 parts of methanol is added alternately, in small portions, 250 partsof 20% aqueoussodium hydroxide and 270 parts of'dimethyl sulfate. The reaction mixture is made alkaline by theaddition of dilute aqueous sodium hydroxide,and-the resultantsolutionextracted with ether. Theorganic layer is washed with water, dried over anhydrous sodium, sulfate, and evaporated to dryness in vacuo. Crystallization of the residue from an ether-hexane solution yields 3-benzyloxy-2-methoxyestra-1,3,5( 10) -trien-17fi-ol which absorbs in'the ultra-violet region at 280 :and 286 millimicrons with extinction coeflicients ioi 3150 and 2900, respectively. .ltsiinfrared absorption spectrum possesses maxirnaat.2.79,=6.18,6.62, 7.98, 9.56 and 9.70microns.

. 'By substituting dibutyl :sulfate'za'nd proceedingaccording to the :he'rein described--.process, 3-benzyloxy-2-butoxyestra-'1',3,5'(10)-trien-17fi-ol'-is obtained. r

EXAMPLES.

1 7,6-aceroxy-3-benzyloxy-Z-methoxyestraJ ,3,5(] 0,)

, triene Amixture'of'S parts of 3 henzyloxyQ-mdhoxyestra l,

solutionto-yield 17fl-acetoxy-3-benzyloxy-2-methoxyestra-1,3,5 101) -triene. The ultraviolet. absorption :spectrum-of this compound contains maxima at.280.5-,an'cl 286.5 millimicrons with extinction coefiicients" of 2950 and280'0, respectively; while'its infrared absorption spectrum possesses maxima at 5.76, 6.18, 6.62, 7.30, 8.01 and 9.72 microns.

By substituting 3-benzyloxy-2-butoxyestra-1,3,5 10) trien-17 3-ol and Valerie anhydride and otherwise proceeding according to the herein described process, 3-benzyloxy-2-butoxy-.17,3-valeryloxyestra-1,3,5(10) ?triene is obtained.

i 1 7[8-acefoxy'-2 ,3 -'dimef h0xyestfa-'1 ,3,"5 (I0) -triene I A solution of Sparts of 2,l7fl-diacet0xy-3-methoxyestra-l ,3,5 (10) -trie'nein 400 'parts "of methanol is stirred at room temperature while 180 parts of 20% aqueous sodium hydroxide and 200 parts of dimethyl sulfate are added. Stirring is .continued for 30 minutes, then the mixture :made alkaline and extracted with ether. The ether layer is washed with water, dried over anhydrous sodium sulfateand the solvent removed under reduced pressure. The solid residue is crystallized from an etherhexane solution to aflord 2,3-dimethoxyestra-1,3,5(10)- trien-17B-ol.

A mixture of 1 part of 2,3-dimethoxyestra-1,3,5(10) trien-17fi-ol, 40 parts of pyridine, and 42 parts acetic anhydride is heated on a steam bath for 16 hours, then poured into parts of water. The resultant mixture is extracted with ether; the organic layer separated and washed successively with water, 2% aqueous sodium hydroxide, and 2% hydrochloric acid solution. The ether solution is dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure. Recrystallization of the residue from an -ether-hexane solution yields 17;? acetoxy-2,3-dimethoxyestra-l,3,5(l 0) triene. Thiscompound possesses maxima in the ultra-violet at 280 and-286 millimicrons with extinction coefficients of .3100 and 2700, respectively; and also, maxima in the infra-red at-5.76, 6.18, 6:63, 7.30, 8.00'and 9.701microns.

Bysubstituting dibutyl sulfate and otherwise proceeding according to 'theherein described processes, 17/3-a'cet- 'oxy 2-butoxy-3-methoxyestra-l,3,5'(10) triene is obtained. Whatis claimed is: I 1. A-compound of the structural formula:

Ha o

wherein R is amembe'r' of thegroup consisting of lower alkyl and benzylradicals, R is selected from the group consisting oflower alkyl and lower alkanoyl radicals, and 'R is.a lower-alkanoyl radical.

2. A compound of the structural formula OR: I

wherein.R is a lower alkyl radical, R isan acetyl radical, and,R is alower alkanoyl radical.

.3. 2,-l7fl-diacetoxya3 methoxyestra-1,3,5 10.) -.triene.

6 4. A compound of the structural formula wherein R is a benzyl radical, R is an acetyl radical, and

H30 R is a lower alkanoyl radical.

' 7. 3-benzyloxy-2,17fl-diacetoxyestra-1,3,S(10)-triene.

' l 8. A compound of the structural formula 5 H30 I CR:

wherein R is a benzyl radical, R is a lower alkyl radical, m0 and R is a lower alkanoyl radical. R O 5. 17p-acetoxy-3-benzyloxy-2-methoxyestra-1,3,5(10)-' triene.

6. A compound of the structm-al for ul wherein R and R, are lower alkyl radicals and R is :1

Has lower alkanoyl radical.

0 9. 17 ,8-acetoxy-2,3-dimethoxyestra-1,3,5 10) -triene.

20 References Cited in the file of this patent UNITED STATES PATENTS Rio 2,846,453 Hoehn Aug. 5, 1958 OTHER REFERENCES Fishman: J.A.C.S., vol. 80, pages 1213-16 (1958). 

1. A COMPOUND OF THE STRUCTURAL FORMULA: 